Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. Dementia is a group of symptoms caused by gradual death of brain cells. The loss of cognitive abilities that occurs with dementia leads to impairments in memory, reasoning, planning, and behavior. While the overwhelming number of people with dementia are elderly, dementia is not an inevitable part of aging; instead, dementia is caused by specific brain diseases. Alzheimer's disease (AD) is the most common cause, followed by vascular or multi-infarct dementia. The prevalence of dementia is difficult to determine, partly because of differences in definition among different studies and partly because there is some normal decline in functional ability with age. The prevalence of dementia roughly doubles for every five years of age beginning at age 60. Dementia affects about 1% of people between ages 60 and 64, 5-8% of all people between ages 65 and 74, up to 20% of those between 75 and 84, and between 30% and 50% of those age 85 and older. About 60% of nursing home patients have dementia.
The Alzheimer's Association estimates that in 2007, 5.1 million Americans were living with a diagnosis of AD. That number expected to grow substantially as the population ages.
The cost of dementia can be considerable. While most people with dementia are retired and are not affected by income losses from their disease, the cost of care often is enormous. Financial burdens include lost wages for family caregivers, medical supplies and drugs, and home modifications to ensure safety. Nursing home care may cost several thousand dollars a month or more. The psychological cost is not as easily quantifiable but can be even more profound. The person with dementia loses control of many of the essential features of his life and personality, and loved ones lose a family member even as they continue to cope with the burdens of increasing dependence and unpredictability.
Dementia usually is caused by degeneration in the cerebral cortex, the part of the brain responsible for thoughts, memories, actions, and personality. Death of brain cells in this region leads to the cognitive impairment that characterizes dementia. The most common cause of dementia is AD, accounting for one-half to three-fourths of all cases. The brain of a person with AD becomes clogged with two abnormal structures called neurofibrillary tangles and senile plaques. Neurofibrillary tangles are twisted masses of protein fibers inside nerve cells (neurons). Senile plaques are composed of parts of neurons surrounding a group of proteins called beta-amyloid deposits. Why these structures develop is unknown. Current research indicates possible roles for inflammation, blood flow restriction, and molecular fragments known as free radicals.
Several genes have been associated with higher incidences of AD, although the exact role of these genes still is unclear. Discovered by researchers at Duke University in the early 1990s, potentially the most important genetic link to AD is on chromosome 19. A gene on this chromosome, called APOE (apolipoprotein E), codes for a protein involved in transporting lipids (fats) into neurons. Certain variations of this gene appear to increase the chance for developing AD and/or lower the age at which symptoms occur. Researchers believe that as many as seven other AD risk-factor genes exist. In 2007, scientists identified a possible risk factor in four new AD-related regions in the human genome. In these regions, one out of several hundred genes may be a risk factor. One gene called SORL 1 has drawn particular research attention. This gene is involved regulating the transport of certain proteins in the cell. As of 2009, the role SORL 1 in the development of AD remained under study.
Vascular dementia is estimated to cause from 5-30% of all dementias. It occurs from decrease in blood flow to the brain, most commonly due to a series of small strokes (multi-infarct dementia). Other cerebrovascular causes include vasculitis from syphilis, Lyme disease, or systemic lupus erythematosus (SLE); subdural hematoma; and subarachnoid hemorrhage. Because of the usually sudden nature of its cause, the symptoms of vascular dementia tend to begin more abruptly than those of Alzheimer's dementia. Symptoms may progress stepwise with the occurrence of new strokes. Unlike AD, the incidence of vascular dementia is lower after age 75.
Conditions that may cause dementia include: AIDS, Parkinson's disease, Lewy body disease, Pick's disease, Huntington's disease, Creutzfeldt-Jakob disease, brain tumor, hydrocephalus, head trauma, multiple sclerosis, prolonged abuse of alcohol or other drugs, vitamin deficiency: thiamin, niacin, or B12, hypothyroidism, and hypercalcemia.
Consequences of Dementia and Alzheimer's Disease
Dementia is marked by a gradual impoverishment of thought and other mental activities. Losses eventually affect virtually every aspect of mental life. The slow progression of dementia is in contrast with delirium, which involves some of the same symptoms, but has a very rapid onset and fluctuating course with alteration in the level of consciousness. However, delirium may occur with dementia, especially since the person with dementia is more susceptible to the delirium-inducing effects of many types of drugs.
Symptoms of dementia include: Memory losses, impaired abstraction and planning, language and comprehension disturbances, poor judgment impaired orientation ability, decreased attention and increased restlessness, behavioral changes and psychosis, depression is common in the elderly and can be mistaken for dementia.
“Alzheimer's disease (AD)”, also known in medical literature and is defined for the purposes of the present invention as the most common form of dementia. There is no cure for the disease, which worsens as progresses and eventually leads to death. Most often, AD is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050. Because AD cannot be cured and is degenerative, the sufferer relies on others for assistance. The role of the main caregiver is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a great burden on caregivers; the pressures can be wide-ranging, involving social, psychological, physical, and economic elements of the caregivers life. In developed countries, AD is one of the most costly diseases to society.
The cause for most Alzheimer's cases is still essentially unknown (except for 1% to 5% of cases where genetic differences have been identified). Several competing hypotheses exist trying to explain the cause of the disease:
Cholinergic Hypothesis
The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.
Amyloid Hypothesis
In 1991, the amyloid hypothesis postulated that beta-amyloid (βA) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age. Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Whilst apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.
Tau Hypothesis
The tau hypothesis is the idea that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
Other Hypotheses
Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene. Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Iron released during myelin breakdown is hypothesised to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as beta-amyloid and tau. Oxidative stress and dys-homeostasis of biometal (biology) metabolism may be significant in the formation of the pathology.
Biochemistry of Alzheimer's Disease
Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD. Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded amyloid beta and amyloid tau proteins in the brain. Plaques are made up of small peptides, 39-43 amino acids in length, called beta-amyloid (Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques. In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.
Pharmacological Approaches for the Treatment of Dementia and Alzheimer's Disease
Treatment of dementia begins with treatment of the underlying disease, where possible. The underlying causes of nutritional, hormonal, tumor-caused, and drug-related dementias may be reversible to some extent. Treatment for stroke-related dementia begins by minimizing the risk of further strokes through smoking cessation, aspirin therapy, and treatment of hypertension, for instance. Alzheimer's disease is, as of 2009, incurable; however, early diagnosis and prompt intervention can slow decline from AD and extend the period during which people the disease can maintain independent functioning. As of 2009, the United States Food and Drug Administration (FDA) had approved five prescription drugs for the treatment of AD symptoms. Four of these are used to treat mild to moderate AD. They are galantamine (Razadyne formerly known as Reminyl), rivastigmine (Exelon), donepezil (Aricept), and tacrine (Cognex). Tacrine, however, is rarely prescribed because of safety issues. These drugs all act by increasing the level of chemical signaling molecules (neurotransmitters) in the brain to help compensate for decreased communication ability among nerve cells. The fifth drug, memantine (Namenda), is used to treat moderate to severe AD. It acts by regulating a chemical in the brain called glutamate.
None of these drugs cure or stop AD. In some individuals, they do slow the progression of symptoms by modestly increasing cognition and improving the individual's ability to perform normal activities of daily living. Slowing or reversing dementia is an area of active research. Clinical trials of new drugs and therapies are ongoing.
Antioxidants, which act to protect against oxidative damage caused by free radicals, have been shown to inhibit toxic effects of beta-amyloid in laboratory tissue cultures. Vitamin E, an antioxidant, is thought to delay AD onset. However, it is not yet clear whether this is due to the specific action of vitamin E on brain cells or to an increase in the overall health of those taking it.
Research is being conducted to determine if vitamin E or other antioxidants may delay or prevent AD.
Ginkgo extract, derived from the leaves of the Ginkgo biloba tree, appeared to be one of the more promising alternative treatments for AD. A 1997 study of patients with dementia seemed to show that ginkgo extract could improve their symptoms, although the study was criticized for certain flaws in its method. Unfortunately, a large-scale, well-designed, follow-up study released in 2008 showed that Ginkgo extract neither prevented nor delayed AD.
Some alternative practitioners advise people with AD to take supplements of phosphatidylcholine, vitamin B12, gotu kola, ginseng, St. John's Wort, rosemary, saiko-keishi-to-shakuyaku (A Japanese herbal mixture), and folic acid. As of 2009, none of these alternative therapies met the safety and effectiveness standards of conventional Western medicine as a treatment for AD. Therefore Dementia Diseases are a significant problem in the world. Although modest advances have been made in dementia detection and treatment, no drug universally successful preventive or therapeutic method is currently available. Unfortunately, that none of the developed and used drugs and method can cure or stop dementia diseases particularly Alzheimer, in both men and women. In the fight against dementia diseases, numerous techniques have been developed and are subject of current research directed to understanding the nature and cause of the disease and to providing methods for the control or cure thereof. Although a number of agents have been evaluated, the prevention and treatment of dementia diseases remains fraught with complications which often present an array of suboptimal treatment choices.
There is a great need for pharmaceutical therapies that can be used to treat patients with the above mentioned disorders, including patients who do not respond to currently available therapies, as well as for pharmaceutical therapies that improve the efficacy of currently available treatment regimes. Pharmacological strategies to have efficacy on the prophylaxis, prevention, attenuation, reduction, elimination and/or therapeutical treatment the symptoms of said dementia and/or Alzheimer's would therefore have an enormous impact on the quality of life (QoL) and on public health.